In the search for therapeutic agents, one of the first steps is to identify specific compounds that bind to the receptor or enzyme target of interest. Once these compounds are identified, numerous analogs or related compounds are synthesized and evaluated for maximum pharmacological activity. Due to the need to synthesize and evaluate large numbers of compounds in an efficient manner, methods have been developed for the generation of large combinatorial libraries of compounds. The first combinatorial libraries generated were those containing peptides and oligonucleotides. However, these compounds generally have poor oral activity and rapid in vivo clearance. Therefore, the utility of these compounds as therapeutic agents is often limited.
Unlike the peptides and oligonucleotides, many small organic compounds, i.e., those with a molecular weight less than 700, have favorable pharmacodynamic and pharmacokinetic properties. Thus, the design, synthesis and evaluation of libraries comprising small organic molecules is at present of major interest in the field of organic chemistry.
Most of the organic chemical libraries generated to date are made using solid-phase synthesis methods. In solid-phase synthesis, the compounds of interest are made on a polymeric solid support material, such as cross-linked polystyrene. There are general advantages to such solid-phase synthesis. First, isolation of the support-bound reaction products is achieved by washing away reagents from the support-bound material, and therefore reactions can be driven to completion by the use of excess reagents. Second, methods are available for the manipulation of discrete compounds and for tracking the identity of compounds when compounds are attached to a solid support. Also, desired products can be easily isolated without the use of expensive chromatographic methods.
In solid-phase synthesis, the compounds of interest are generated while attached to the solid support via a linkage element, or "linker." Ideally, the linker should be stable to all reactions used in a synthesis sequence and should be cleaved quantitatively under conditions that do not degrade the desired target compounds.
Linkage strategies are generally grouped into four categories. The first is to link through functionality already present in the desired target compounds, as is done in peptide and oligonucleotide synthesis. The second strategy is a cyclative cleavage whereby the linker is incorporated into the final compound. In many cases, however, these two strategies cannot be used with a desired class of compounds or these strategies limit the chemistry that can be performed. Therefore, the third and more general strategy is to introduce an auxiliary functional group, such a phenol, amide, or carboxylate, as a handle for the linker attachment. After cleavage from the solid support when synthesis is complete, this functional group can have a negligible, positive, or negative effect on the biological or chemical activity of the target compounds, depending on the location of the functional group. Thus, this approach introduces an undesirable degree of unpredictability to the synthesis.
An alternative fourth approach is to use a linker that can be removed efficiently and quantitatively when desired, leaving behind no trace of the solid-phase synthesis. One such linker is a silicon-based linker, from which the compounds of interest can be separated by protodesilation, to leave no trace of the linkage site. Various silicon-based linkers have been disclosed in the literature. In J. Org. Chem., 1976, 41, 3877, a dimethylchlorosilane linker is disclosed. This linker is anchored to a solid support, such as a styrene-divinylbenzene copolymer. However, the synthesis scheme disclosed to generate this polymer-anchored linker has not been found to be reproducible. Moreover, the linker is not stable under standard storage conditions, because the silyl chloride is highly susceptible to hydrolysis.
A diphenylchlorosilane linker is disclosed in J. Chem. Soc., Chem. Commun., 1985, 909. Again, this linker is attached to a styrene-divinylbenzene copolymer. Due to the presence of the chloro group, this linker suffers from the same stability problems as the linker discussed above. In J. Org. Chem., 1995, 60, 6006 a silyl-substituted (aminoaryl)stannane ester derivative linker is disclosed. However, synthesis of this linker is complicated and requires that the linker be separately produced before it is joined to the solid support.
Accordingly, a need exists for a solid support linker compound for use in solid-phase synthesis that is stable under storage conditions, but also that can easily be rendered highly reactive. A need also exists for a linker that can be easily produced on solid support. Further, a need exists for a solid support linker that can be readily isolated and purified in high yields. These needs are met by the silicon-based solid support linkers of the present invention.